Title |
GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway
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Published in |
PLoS Genetics, February 2017
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DOI | 10.1371/journal.pgen.1006609 |
Pubmed ID | |
Authors |
Krzysztof Kiryluk, Yifu Li, Zina Moldoveanu, Hitoshi Suzuki, Colin Reily, Ping Hou, Jingyuan Xie, Nikol Mladkova, Sindhuri Prakash, Clara Fischman, Samantha Shapiro, Robert A. LeDesma, Drew Bradbury, Iuliana Ionita-Laza, Frank Eitner, Thomas Rauen, Nicolas Maillard, Francois Berthoux, Jürgen Floege, Nan Chen, Hong Zhang, Francesco Scolari, Robert J. Wyatt, Bruce A. Julian, Ali G. Gharavi, Jan Novak |
Abstract |
Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 4 | 36% |
United Kingdom | 3 | 27% |
Spain | 1 | 9% |
India | 1 | 9% |
Unknown | 2 | 18% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 5 | 45% |
Practitioners (doctors, other healthcare professionals) | 3 | 27% |
Scientists | 2 | 18% |
Science communicators (journalists, bloggers, editors) | 1 | 9% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 74 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 14 | 19% |
Student > Bachelor | 10 | 14% |
Student > Ph. D. Student | 9 | 12% |
Student > Master | 7 | 9% |
Student > Doctoral Student | 4 | 5% |
Other | 11 | 15% |
Unknown | 19 | 26% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 21 | 28% |
Biochemistry, Genetics and Molecular Biology | 10 | 14% |
Agricultural and Biological Sciences | 8 | 11% |
Nursing and Health Professions | 3 | 4% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 3% |
Other | 7 | 9% |
Unknown | 23 | 31% |